Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

SOHO State of the Art Updates and Next Questions: Prophylaxis and Management of Secondary CNS Lymphoma.

Secondary CNS lymphoma (SCNSL) is a rare but frequently fatal complication of systemic lymphoma. There is no standard treatment for SCNSL, and patients who develop SCNSL at diagnosis or after frontline therapy often receive highly intensive chemotherapy regimens that are inactive against primary chemorefractory disease and too toxic for older, frail patients to tolerate. Because the prognosis of SCNSL is so poor, management has historically emphasized prevention, but the current methods of CNS prophylaxis are not universally effective. To improve both the prevention and management of SCNSL, better characterization of the molecular determinants of CNS invasion is needed. Novel treatments that are currently being studied in SCNSL include targeted pathway inhibitors and cellular therapy, but SCNSL patients are often excluded from clinical trials of promising new therapies.

Secondary vitreoretinal lymphoma with spontaneous regression.

PURPOSE: To report a patient with vitreoretinal lymphoma (VRL) secondary to systemic diffuse large B-cell lymphoma, who had two episodes of spontaneous regression. OBSERVATIONS: An 80-year-old Nicaraguan male with a history of treated systemic diffuse large B-cell lymphoma presented with decreased vision in his right eye over one year. The patient was found to have subretinal lesions and moderate vitreous opacities in his right eye. Cytological analysis of vitreous confirmed B-cell lymphoma. Following his systemic work-up, spontaneous clinical improvement was noted. There were no vitreoretinal or systemic lymphoma recurrences during one year of follow-up until the patient had new onset decreased vision in the left eye. He was presumed to have a recurrence of VRL supported by optical coherence tomography findings. Repeat systemic workup was negative for reoccurrence and the ocular lesions resolved spontaneously over 4 weeks. CONCLUSIONS: Spontaneous regression of intraocular lymphoma can rarely occur. Multimodal imaging has an essential role in diagnosing and monitoring recurrence of this disease.

Survivorship Guidance for Patients with Colorectal Cancer.

OPINION STATEMENT: Effective therapy for treatment of colorectal cancer includes comprehensive and evidence-based therapies that may include a combination of surgery, chemotherapy, targeted therapy, and/or radiation. However, in order to provide patients with the highest quality of care, providers must consider all aspects of survivorship care including: surveillance for recurrence/second primaries, genetic counseling, psychosocial/physical late effects of cancer and its therapies, and preventative lifestyle strategies. Health systems, providers, and researchers need to identify systematic methods of addressing the unique needs of the survivorship population that include multidisciplinary teams including supportive oncology (i.e., psychologists, social workers), specialties (i.e., cardiology), and primary care physicians.

Pseudoprogression of Melanoma Brain Metastases.

PURPOSE OF REVIEW: Immune checkpoint inhibitors are increasingly being used to treat melanoma brain metastases. One potential complication of immune checkpoint inhibitors is a phenomenon called pseudoprogression, in which a tumor transiently increases in size due to lymphocyte infiltration. This article reviews the characteristics of pseudoprogression and their clinical implications. RECENT FINDINGS: Pseudoprogression can be challenging to differentiate from true progression noted clinically or radiographically, thereby complicating management decisions and potentially confusing patients and their families. The transient tumor enlargement can also cause symptoms that mimic true tumor progression. Because the use of immunotherapy on melanoma brain metastases is a relatively new treatment paradigm, there is limited evidence to guide clinical decision-making and prognostication related to pseudoprogression.

Screening for Recurrence and Secondary Cancers.

The population of adult cancer survivors is increasing over time and they are at risk of developing recurrent and secondary cancers, even years after completion of treatment. Post-treatment care of survivors is increasingly the responsibility of primary care providers. Surveillance for recurrence and screening for secondary malignancies related to treatment depend largely on the primary malignancy, treatment regimen, and presence of a hereditary cancer syndrome, such as a BRCA mutation. This article presents surveillance strategies for the most common malignancies.

Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products.

Discovery and in vivo evaluation of dual PI3Kß/δ inhibitors.

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.